Genomewide search for type 2 diabetes-susceptibility genes in French whites: Evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24

Despite recent advances in the molecular genetics of type 2 diabetes, the m ajority of susceptibility genes in humans remain to be identified. We there fore conducted a 10-cM genomewide search (401 microsatellite markers) for t ype 2 diabetes-related traits in 637 members of 143 French pedigrees ascert ained through multiple diabetic siblings, to map such genes in the white po pulation. Nonparametric two-point and multipoint linkage analyzes-using the MAPMAXER-SIBS (MLS) and MAXIMUM-BINOMIAL-LIKELIHOOD (MLB) programs for aut osomal markers and the ASPEX program for chromosome X markers-were performe d with six diabetic phenotypes: diabetes and diabetes or glucose intoleranc e (GI), as well as with each of the two phenotypes associated with normal b ody weight (body-mass index<27 kg/m(2)) or early age at diagnosis (<45 year s). In a second step, high-resolution genetic mapping (similar to2 cM) was performed in regions on chromosomes 1 and 3 loci showing the strongest link age to diabetic traits. We found evidence for linkage with diabetes or GI d iagnosed at age <45 years in 92 affected sib pairs from 55 families at the D3S1580 locus on chromosome 3q27-qter using MAPMAKER-SIBS (MLS = 4.67, P = .000004), supported by the MLB statistic (MLB-LOD = 3.43, P = .00003). We a lso found suggestive linkage between the lean diabetic status and markers A POA2-D1S484 (MLS = 3.04, P = .00018; MLB-LOD = 2.99, P = .00010) on chromos ome 1q21-q24. Several other chromosomal regions showed indication of linkag e with diabetic traits, including markers on chromosome 2p21-p16, 10q26, 20 p, and 20q. These results (a) showed evidence for a novel susceptibility lo cus for type 2 diabetes in French whites on chromosome 3q27-qter and (b) co nfirmed the previously reported diabetes-susceptibility locus on chromosome 1q21-q24. Saturation on both chromosomes narrowed the regions of interest down to an interval of <7 cM.